TY - JOUR
T1 - Disparate Mutations Confer Therapeutic Gain of Hsp104 Function
AU - Jackrel, Meredith E.
AU - Yee, Keolamau
AU - Tariq, Amber
AU - Chen, Annie I.
AU - Shorter, James
N1 - Funding Information:
We thank A. Gitler, S. Lindquist, B. Johnson, and M. Duennwald for kindly sharing reagents, and K. Mack and M. Torrente for critiques. Our studies were supported by an American Heart Association Post-Doctoral Fellowship and Target ALS Springboard Fellowship (M.E.J); NIH Director’s New Innovator Award DP2OD002177, NIH grants R21HD074510 and R01GM099836, a Muscular Dystrophy Association Research Award (MDA277268), Packard Center for ALS Research at Johns Hopkins University, Target ALS, an Ellison Medical Foundation New Scholar in Aging Award, and The Life Extension Foundation (J.S.).
Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/10/5
Y1 - 2015/10/5
N2 - Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or α-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity.
AB - Hsp104, a protein disaggregase from yeast, can be engineered and potentiated to counter TDP-43, FUS, or α-synuclein misfolding and toxicity implicated in neurodegenerative disease. Here, we reveal that extraordinarily disparate mutations potentiate Hsp104. Remarkably, diverse single missense mutations at 20 different positions interspersed throughout the middle domain (MD) and small domain of nucleotide-binding domain 1 (NBD1) confer a therapeutic gain of Hsp104 function. Moreover, potentiation emerges from deletion of MD helix 3 or 4 or via synergistic missense mutations in the MD distal loop and helix 4. We define the most critical aspect of Hsp104 potentiation as enhanced disaggregase activity in the absence of Hsp70 and Hsp40. We suggest that potentiation likely stems from a loss of a fragilely constrained autoinhibited state that enables precise spatiotemporal regulation of disaggregase activity.
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U2 - 10.1021/acschembio.5b00765
DO - 10.1021/acschembio.5b00765
M3 - Article
C2 - 26441009
AN - SCOPUS:84951920497
SN - 1554-8929
VL - 10
SP - 2672
EP - 2679
JO - ACS chemical biology
JF - ACS chemical biology
IS - 12
ER -